The etiology of many respiratory diseases has remained unclear in spite of direct attempts to determine factors that lead to pulmonary damage and loss of function. The underlying respiratory inflammation leading to variable airflow limitation and airway hyperresponsiveness to various stimuli in some respiratory diseases can be exacerbated by allergens, respiratory tract infections, or environmental agents. Localized cytokine/chemokine gene expression (King et al., Am J. Respir. Cell & Mol. Biol., 14, 319 (1996)), secretion of low molecular weight inflammatory mediators (Henderson, Ann. Allergy, 72, 272 (1994)), and the recruitment of specific leukocyte cell types (Bentley et al., J. Inv. Allerzol. Clin. Immunol., 4, 222 (1994)) have all been shown to contribute to respiratory inflammation. For example, asthma is a multifactorial syndrome characterized by breathlessness, pulmonary constriction, airway hyperreactivity and mucous accumulation. It is often, but not always associated with allergies (extrinsic) or environmental stimuli, e.g., tobacco smoke.
Many pathophysiological manifestations of asthma are associated with airway infiltration by eosinophils and lymphocytes. This infiltration is mediated by cytokines and chemokines. Leukocyte influx, in turn, has been associated with the development of lung dysfunction, even in nominal cases of asthma. Indeed, the extent of infiltration generally correlates with the severity of disease. Antigen-induced mouse models of pulmonary allergic disease have proved particularly informative in the genetic dissection of inflammatory pathways in the lung. Typically, these models involve sensitization with a specific antigen (e.g., ovalbumin) followed by airborne administration of the same antigen. Sensitized mice treated with aerosolized allergen develop leukocytic infiltrates of the airway lumen dominated by CD4+ lymphocytes and eosinophils. These mice also develop many of the changes pathognomonic of asthma, including airway hyperresponsiveness (AHR) and goblet cell hyperplasia with excessive mucus production.
The cellular signals leading to airway inflammation, eosinophil infiltration, and AHR remain obscure. Lymphocytes, eosinophils, and mast cells have been implicated in the AHR of antigen-challenged mouse models of asthma. SCID mice, which lack both T and B lymphocytes, fail to develop either an airway eosinophilia or bronchial hyperreactivity after ovalbumin sensitization (Corry et al., J. Exp. Med., 183, 109 (1996)). The depletion of CD4+ lymphocytes, either by treatment with anti-CD4 antibodies or MHC Class II gene knock-out, eliminated both eosinophil airway infiltration and AHR in antigen-challenged mice (Garett et al., Am. J. Respir. Cell & Mol. Biol., 10, 587 (1994)). In contrast, depletion of CD8+ T lymphocytes with anti-CD8 antibodies had no effect on lung eosinophil infiltration but eliminated AHR (Nakajima et al., Am. J. Respir. Cell & Mol. Biol., 10, 587 (1994); Hammelmann et al., J. Exp. Med., 183, 1719 (1996)). Moreover, studies with mast cell deficient mice (W/W.sup.v) indicated that mast cells were not specifically required for either eosinophil airway infiltration or AHR (Bruselle et al., Am. J. Respir. Cell & Mol. Biol., 12, 254 (1995)).
Collectively, the antigen sensitization and challenge mouse models implicate T-lymphocytes as a component of the inflammatory response. Furthermore, IL-4 or IL-5 cytokine gene knock-out studies using aerosolized antigen challenge suggest that IL-4 and IL-5 are each important components of proinflammatory cascades that ultimately result in eosinophil airway infiltration and pathophysiological changes characteristic of asthma (Bruselle et al., supra; Foster et al., J. Exp. Med., 183, 195 (1996)).
To define the role of IL-5 in vivo, Dent et al. (J. Exp. Med., 172, 1425 (1990)) prepared transgenic mice in which transcription of a genomic copy of the IL-5 gene was under the transcriptional regulatory influence of the dominant control region (DCR) of the gene encoding human CD2 (a T cell surface antigen). Although Dent et al. showed that serum IL-5 levels were elevated in transgenic mice (Tg5C2), because the CD2 enhancer element is only weakly active in mature peripheral T cells, the elevation in serum IL-5 levels was primarily due to thymocyte expression and not peripheral T cell expression. In contrast, serum IL-5 levels are elevated in parasite infested (Mesocestroides corti) or antigen challenged mice as a result of IL-5 expression by peripheral T cells. Moreover, despite the increase in serum IL-5 levels, the Tg5C2 mice showed no symptomatic effects of IL-5 overexpression other than a mild splenomegaly and an eosinophilia accompanying a 7-fold increase in white blood cell (WBC) count.
Tominaga et al. (J. Exp. Med., 173, 429 (1991)) disclose that transgenic mice in which a IL-5 cDNA was linked to the mouse metallothionein promoter (Tg-6 mice) demonstrated a peripheral eosinophilia with a 3-fold increase in total WBCs. Serum IL-5 levels in Tg-6 mice were 16,000 pg/ml. The predominant sites of IL-5 expression in these mice were the kidney and liver. These organ sites are not normally associated with the production of IL-5 and thus fail to mimic the necessary microenvironmental cues that occur in peripheral sites. Thus, the lack of significant physiological effects in these mice may be the result of ectopically produced IL-5.
Thus, a need exists for an animal model that constitutively expresses IL-5 in a tissue and/or cell-type specific fashion. Moreover, a need exists for an animal model that constitutively expresses IL-5 in thymocytes and peripheral T cells, or in lung tissue, so as to result in IL-5 induced pathologies.